Major depression is associated with a doubling of mortality and cardiovascular disease at any age, independent of smoking and other risk factors for poor health. We first reported that patients with major depression have premature osteopenia and osteoporosis that was marked even in premenopausal women. We have made significant strides in elucidating pathophysiological mechanisms of relevance to both processes. Our studies have identified dysregulations in a network of metabolic, endocrine, hemostatic, inflammatory, and autonomic processes that independently and synergistically contribute to premature coronary artery disease. Some of these correspond to those specified in the World Health Organization's (WHO) criteria for the Metabolic Syndrome, consisting of insulin resistance and its sequella, including hypertension and dyslipidemia. In addition to these abnormalities we have also identified other sequella of insulin resistance such as increased inflammation, coagulation, and activation of the sympathetic nervous system. Specifically, we have found: Metabolic - insulin resistance, hyperinsulinemia, and hyperglycemia in a large group of well matched patients with major depression. The Clinical Neuroendocrinology Branch has made major advances in two fundamental areas of relevance to the premature mortality reported in patients with major depression. We have first identified an interrelated network of autonomic, endocrine, metabolic, and hemostatic abnormalities that independently and synergistically promote atherosclerosis. Several of these abnormalities correspond to what the WHO has designated, the Metabolic, or Insulin Resistance Syndrome, a cluster of metabolic, endocrine, abnormalities that induce arterial and small blood vessel damage. We have identified alterations in patients with major depression that include: 1) insulin resistance; 2) hyperinsulinemia; 3) hyperglycemia; 4) loss of lean body mass and increased adiposity; and (5) dyslipidemia. We also found that our patients have significant increases in factor VIII, a coagulation factor stimulated by high insulin levels. Because insulin also stimulates the secretion of the proinflammatory cytokine IL-6, we measured this compound serially around the clock. The levels of IL-6 are highly elevated around the clock, and for many hours exceed the 2.9 pg/ml cutoff that is predictive of increased risk for coronary artery disease. We also found that our patients have increased levels of CRP, shown to increase the relative risk of heart disease by a factor of at least 3. There are many potentially useful interventions for the metabolic syndrome, heightening the urgency of making the diagnosis and instituting treatment for major depressive illness. In addition to components of the metabolic syndrome, we have also found that drug-free patients with severe melancholic depression have significant increases in blood pressure and pulse rate, as well as significant around-the-clock elevations of plasma and CSF NE levels (assessed hourly for thirty continuous hours). These patients also had significant around-the-clock elevations in plasma epinephrine. These parameters returned to normal levels after electroconvulsive treatment. The fact that the levels of these compounds were highest at night and early in the morning, indicate that our findings are independent of the conscious distress of the disorder. We also found that less severely depressed drug free patients with melancholic depression had significant increases in total body norepinephrine spillover at rest and in response to psychological and pharmacological stressors. We have reported that over 20% of premenopausal women with major depression have osteopenia, 6% meet criteria for osteoporosis, rendering them at greater risk for fracture. Given the incidence of major depression in women, these data results predict that almost 360,000 premenopausal women have osteoporosis related to major depression. Osteoporosis is a silent condition and becomes manifest after a fracture has occurred. We have also shown that premenopausal women with major depression and osteoporosis respond well to alendronate, a compound that inhibits bone resorption. The widespread availability of this very safe compound heightens the importance of identifying and treating the premature bone loss of major depression early.